Tumor-associated mutations in the FA (Fanconi anemia) genes offer exciting opportunities for chemoprevention, diagnosis, and tailored therapy for pancreatic, ovarian, and breast cancer. No cancer type has a higher proportion of FA-mutated tumors than pancreatic cancer. A decade ago, we initiated the first registry of pancreatic cancer families having FA mutations. We found mutations in BRCA2, FANCC, and FANCG in pancreatic cancers, a classic example of a high-frequency low-penetrance population risk with high clinical importance. The FA gene mutations convey a hypersensitivity to certain drugs and radiation, but clinically important questions arose when we observed the level of sensitivity to differ, depending on which FA gene was mutated. We recently initiated a trial to treat FA-deficient cancers using a drug to which they are specifically hypersensitivity. To our knowledge this is the first U.S. clinical cancer trial in which the indicated drug is specified by an analysis of germline DNA mutations. Yet, the laboratory components of the trial and its design have never attained funding by a specific grant. Considerable improvements in trial design are likely if translational research aims can be pursued at an appropriate pace. Interest in the correct classification of deleterious mutations is raised by our experience with familial registry and the new trial. We encounter many inherited missense germline FA gene mutations of unclassified significance. They are very common within the general population, but for most it is not known whether they are normal polymorphisms or cancer-causing. We recently explored key technical breakthroughs to better to permit diagnosis and testing of FA defects, and cellular models accelerating this research. Our specific aims employ a new experimental model of somatic cell FA genes knockouts and knock-in of missense variants in cancer cells, generating and evaluating mutation-specific and gene-specific phenotypes and aiding patient management through improved diagnostic and allele-interpretive techniques. Our long-term goal is to understand the roles of FA defects in tumor progression, to understand with precision the distinctions among clinically relevant phenotypic changes produced by different gene mutations, and to identify clinically important patient subgroups. PUBLIC HEALTH RELEVANCE: The most common known causes of familial pancreatic cancer are mutations in a Fanconi gene (specifically, BRCA2). We found mutations of BRCA2 and other Fanconi genes in pancreatic cancers;the mutations are of high clinical importance, for they determine the risk of developing cancer and now also sometimes determine the treatment protocol to which a patient can enroll. Recent advances will allow us now to efficiently explore improved diagnosis and therapeutic assignment of these patients.